The RAS/RAF/MEK/ERK (or “RAS”) and PI3K/AKT/PTEN/mTOR (or “PI3K”) signaling pathways play an important role in the initiation and progression of tumors. The RAS pathway is known to be dysregulated through genetic mutations in RAS, RAF or MEK genes, which leads to increased cell proliferation and angiogenesis. These genetic mutations have been found in wide variety tumors, and inhibition of any of these targets was found to inhibit the growth of tumors both in preclinical animal models and in humans. Similar to the RAS pathway, perturbations in the PI3K pathway also plays an important role in tumor progression, specifically in promoting the tumor cell survival and proliferation. This pathway is dysregulated through genetic changes in the PI3K, AKT and PTEN genes.
Despite some promising initial results in humans, compounds designed to inhibit either the RAS or PI3K pathway are not able to provide a durable therapeutic response, due to drug resistance acquired by the tumor cells from activation of the alternative pathway in the targeted cells. For example, the inhibition of the PI3K pathway with agents such as temsirolimus leads to the subsequent activation of the RAS pathway, resulting in tumors which do not respond to this agent. Conversely, inhibition of the RAS pathway with agents such as vemurafenib leads to the activation of PI3K pathway and the development of drug-resistant tumor cells.
Preclinical data obtained using different combinations of two agents, each inhibiting either the RAS or PI3K pathways, has demonstrated that the simultaneous inhibition of these pathways gives a greater and more durable tumor growth inhibition. However, combining two different agents in this manner can produce the significant disadvantages of added toxicity and higher cost for any subsequently developed drug. Single compounds with dual inhibitory activity against both pathways have since been discovered; see, for example, U.S. Pat. No. 9,499,495 of Thompson et al, “Quinazolines and Azaquinazolines as Dual Inhibitors of RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/MTOR Pathways.” Such compounds avoid the disadvantages of drugs which combine two separate inhibitory compounds. Thus there is a need for stable formulations of single compounds which regulate both the RAS and PI3K pathways, which can be incorporated into dosage forms and kits, all of which can be used in methods treating cancers characterized by the presence of solid tumors.